Approximately 60% of people in the United States are infected with herpes simplex virus type 1 (HSV-1) and 20% with HSV-2. Prophylactic therapy with acyclovir or valacyclovir reduces the rate of cold sore (herpes labialis) recurrences by 40% to 60% and the rate of genital herpes reactivation by 70% to 80%. Thus, other approaches to reduce reactivation of HSV are needed. Control of reactivation of HSV correlates with virus-specific T cells. Increased T cell function might reduce virus reactivation. Nutrients, including glucose and certain amino acids, are critical for T cell activation. Activated T cells require increased metabolism of glutamine for proliferation, and deprivation or inhibition of synthesis of these glutamine reduces T cell proliferation. We found that supplementation with oral glutamine reduced virus reactivation in latently HSV-1-infected mice and HSV-2-infected guinea pigs. Analysis of host cell gene expression of trigeminal ganglia from latently HSV-1-infected, glutamine-treated WT mice showed upregulation of several IFN-gamma-inducible genes. In contrast to WT mice, supplemental glutamine was ineffective in reducing the rate of HSV-1 reactivation in latently HSV-1-infected IFN-gamma-KO mice. Mice treated with glutamine also had higher numbers of HSV-specific IFN-gamma-producing CD8 T cells in latently infected ganglia. Thus, glutamine may enhance the IFN-gamma-associated immune response and reduce the rate of reactivation of latent virus infection.